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Margaret A. Hamburg, M.D., Commissioner of Food and Drugs - AAAS

Remarks of Margaret A. Hamburg, M.D.
Commissioner of Food and Drugs
at
AAAS - The Future of Personalized Medicine
October 26, 2009

I am honored to appear on this program with such an impressive list of speakers. It is a particular privilege for me to be on this morning’s program following Dr. Francis Collins. As one of the true pioneers in the field of genomics, he has the unique ability to inform and illuminate our thinking as we consider the challenges before us in translating the promise of the bench to the bedside.

I hope that you will forgive me if I am a little less technical than Dr. Collins in my remarks, but I must say I look forward to working closely with Dr. Collins-and learning from him as we discover new ways for NIH and FDA to collaborate in shaping research regulatory policy with an eye toward maximizing the benefit to patients.

I have had many long standing connections to AAAS, but this is the first opportunity I’ve had to come here AAAS as FDA Commissioner and I look forward to many future meetings focused on other fascinating and timely topics.

Thanks also to FDLI, the co-sponsor of this colloquium. I truly appreciate your efforts to provide on-going training in the increasingly complex arenas of food and drug law, regulatory policy, and science.

As you heard in my introduction, I have served in many previous public health roles including positions within the National Institutes of Health and the Department of Health and Human Services, but I must say I have been on a very steep learning curve at the FDA.

I really did not have a deep understanding or appreciation for the vast scope and complexity of the FDA’s regulatory mission, until I assumed leadership of the agency five months ago. It has been one of the most intense and enriching learning experiences of my life, and also, at times, a bit overwhelming.

Of the many jobs an FDA Commissioner takes on in the course a single day, week or month, I’ve decided that there are two roles that I must fulfill in order for the FDA to overcome the challenges ahead and perform its mission protecting the public health in a manner equal to the expectations we all hold: advocate and zealot.

First and foremost, I will be a vocal advocate for the FDA and its unique and critical mission. Given how vast and complex nature of the regulatory mission we must accomplish each and every day, I know this agency has been underfunded and underfunded for far too long. We must reverse that trend, and as FDA Commissioner I will work hard every day to secure the resources the FDA needs to perform its critical mission of promoting and protecting the health of the American people.

In order to deliver the promise of scientific discovery to patients and consumers, I have found that I am increasingly becoming a zealot for the advancement of regulatory science. Now, I admit that I have been warned—more than a few times—that when I choose to speak at length about regulatory science I run the risk of looking out over the audience and seeing many eyes glazed over in boredom. But since I am speaking to a group of scientists I think we are on safe ground this morning.

As a science based, science-led regulatory agency, the FDA must respond to the extraordinary advances in new science and technology which offer great new opportunities, but also challenges to our capacity for research, development and regulatory processes.

As we endeavor to translate the great promise of the new science and technology into real-world products for those who need them, it is essential that we have a regulatory agency that is scientifically robust and trusted by the policy makers and the American people.

We must be able to understand and respond to the full range of innovative new products that will come before us, and we must leverage advances in science and technology to ensure that our regulatory systems are as effective and efficient as they can possibly be.

Just as biomedical research has evolved in the past decade, regulatory science – the science and tools we use to assess and evaluate a product's safety, effectiveness, potency, quality and performance – must also evolve.

Our regulatory scientists must be able to understand therapies that are being developed using the most recent scientific advances. They must have the right tools to evaluate these therapies. And they must be a partner to the greater scientific community as they work to bring these therapies to patients.

And I want to underscore the point that we are all in this together. Our nation has invested billions of dollars in biomedical research – an effort that is indispensable for medical progress – but this research will not result in cures unless it is married to a robust investment in regulatory science.

We cannot afford to have a robust investment in fundamental biomedical research and discovery but only a scrawny counterpart investment in regulatory science and in the FDA’s regulatory capacity.

Imagine a rower with an enormous, muscular right arm and a scrawny, atrophied left arm . . . no surprise if the boat ends up going in circles. We need forward progress, and our efforts will be seriously compromised if we don’t significantly increase the sophistication of our regulatory science soon.

A robust, state-of-the-art regulatory science disciple is essential to FDA's work. But more than that, it represents an important driver of our nation's health, the health of our health care industry, and the health of our economy. It is a field of endeavor that must be fully embraced by academia, industry and government.

I consider myself truly fortunate to have the opportunity to lead the FDA through this period of transition and change. It is a dynamic time not only for the agency, but for our country. And given the topic of this meeting, I think we all agree that it is dynamic time in the world of scientific discovery and medical product development.

This first decade of the 21st century began with the decoding of the human genome—a scientific achievement that we knew had the potential to transform our understanding of health and disease and revolutionize our fundamental approach to medicine.

We understood that this breakthrough would lead to the development of new and better therapies and a finer attention of risk and benefit, if not for every single patient, perhaps for patients who reside in particular, identifiable patient sub-populations.

As the decade draws to a close, those of us intensely interested in scientific discovery are somewhat like a family on a car trip. We have been traveling on the road to the future, always glancing in the rear-view mirror measuring how far we’ve come since the point of revolutionary discovery, while trying to keep our sights set on our destination.

And throughout the journey we have been asking the questions—or being asked—the questions: Are we there yet? If not, why not? How long until we arrive? And what do we have to do to get there?

These are great questions. And I’m sure we will continue asking them well into the nest decade. Because in the few short years since we cracked the human genetic code, we’ve come to understand that while that scientific achievement was revolutionary in nature, our path toward realizing all of its potential for medical treatment is evolutionary,and generally incremental, and certainly much slower than we might have wanted.

At the dawn of the atomicage, Albert Einstein said, “everything has changed except for our way of thinking.” In these, the early days of the genomic age, we are trying to adapt our thinking, our regulatory system, our models of drugs development, research, clinical trials and the very way we look at, gather and analyze data to a new reality.

The process of shifting paradigms and creating new models is not easy. But I’m sure that the reason that most of you are here today is that you agree that it is very exciting to be involved in the process helping to transform the way we think about genomics and its application to the discovery of new medical therapies in these still early days.

And I can’t imagine a better vantage point than the one, I feel privileged to have, as the Commissioner of the Food and Drug Administration, because, in my view, the FDA is at the nexus of translating genomics into targeted therapies and new diagnostics, which can lead to better outcomes for patients.

As scientists and physicians, we owe a great deal to the randomized, controlled clinical trials methods which helped move medicine from the realm of anecdote to evidence over the course of the last half century.

These methods have given us the therapeutic advances that have increased longevity and transformed often debilitating and fatal diseases, like diabetes, AIDS, and rheumatoid arthritis into chronic, yet manageable, conditions.

While the evidence-based method gave us great confidence that the clinical trail data we were evaluating gave us a reliable picture of the benefits and potential risks of a new medical product, we have always known that these methods are not infallible; that particular risks may emerge in the post-market population that we frankly did not see and, perhaps, could not detect in the evaluation of a new drug.

The shortcomings in our ability to reliably predict particular adverse events and identify lack of response in some patients had to do with the inherent limits of the testing methodologies.

While we might have a statistically accurate picture, it lacked the nuance we really need to account for human variability. And a statistical average fails to recognize the fundamental truth that patients aren’t really homogeneous populations or sub-populations at all, but individuals.

In terms of answering the critical questions we must ask in any trial for a new molecular entity, the randomized controlled trial could give us the “what” –a quantifiable measure of the effectiveness of a particular drug therapy, but it could not tell us the “why”—why do these patients respond to this treatment and others don’t, and it could not tell us the “who” –who are the responders, and what is the underlying biology that enables them to have this response.

In fact, in some cases, looking at the average response rate for a particular group of patients may provide a false picture, if instead of one group, the data actually reflects the response rates of different sub-groups as identified by genetic variant. For example, a 60 percent response rate may, in fact, be the combination of one patient group with an 80 percent response rate and another patient group with only 40 percent.

Clearly, we can have much better outcomes for patients if we can discern what distinguishes one group from another, in terms of positive response, and design a clinical trail based on that knowledge.

Consider the task of FDA reviewers who must evaluate the scientific data to determine whether an investigational new drug is “safe and effective for its intended use.”
Making this decision has always involved striking a delicate balance.

Erring on one side may mean exposing patients to an unacceptably high risk of adverse events, erring on the other side may mean depriving patients of a therapy they really need for a condition which may cause pain, debilitation or death. These kinds of decisions require advanced training in medicine, science and related fields. They also require skill, depth of experience and some traits that aren’t always identified as essential requirements for government service but are pretty key: wisdom, common sense and good judgment.

But the application of genomics to the field of clinical pharmacology—pharmacogenomics —means that we can put morescience and certainty into the regulatory process of reviewing and approving new drugs and biologics. Perhaps then we can see more new drug applications in the pipeline that are more likely to succeed, because the investigators have identified the biomarkers which characterize the patient sub-population most likely to respond to a new therapy.

Perhaps even more important--and this is critical to all of us who care deeply about protecting the public from harm—is the ability to identify those patients most likely to suffer a severe adverse reaction to a new drug before it reaches the market.

Although a serious adverse reaction to a new drug may be a relatively rare event, it is a catastrophe for those few individuals and their families. And even a relative few severe adverse events, may cause the FDA to have to withdraw a therapy from the market that offers a tremendous benefit to a great deal of patients, if we can not find a reliable way to identify the at-risk patients and exclude them from the treatment population.

We have seen some very encouraging examples of how the FDA is applying the science of pharmacogenomics to drug and device review and post-market safety.

The HIV drug Abacavir showed very good response rates for many patients, but a relative few patients suffered severe adverse reactions which included fever, gastrointestinal and respiratory distress. But once we could identify the at-risk patient population by the presence of a genetic variant call HLA-B 5701, we could seek to exclude them from the patient population. The drug label now carries the warning that patients with this variant are at risk for severe adverse reactions. As a result, clinicians can now prescribe the drug for their patients with confidence following a test for that genetic variant.

On the benefit side, the label for two FDA-approved colon cancer drugs now contain the recommendation that patients should be tested for the presence of the K-RAS mutation before starting therapy with those drugs because, as we now know, patients with that genetic mutation are highly unlikely to see a positive response from those therapies.

And this is important because when patients are battling cancer they don’t have time for trial and error; prescribing an ineffective course of treatment not only wastes precious time in the fight against a potentially fatal disease progression, the toxicity from the exposure to an ineffective therapy can undermine their efforts.

In order for the FDA to build on the promise that personalized medicine holds for new and better therapies; in order to better calibrate the risk/ benefit for drugs already on the market; the FDA must take a more holistic approach to its role in the process. For medical products that result in the application of personalized medicine, in addition to the roles of “reviewer” and “regulator” FDA, must also serve as a “catalyst” for innovation.

This involves, among other things, increased outreach and collaboration with industry, academia and our government research colleagues. For example, FDA’s Center for Drug Evaluation recognized early on that in order for companies to make a serious investment in genomics, they had to believe that FDA was serious about the science and learning how to incorporate it into the medical product review process. In 2003, the center established a Voluntary Data Exchange program and asked companies to voluntarily submit to the agency genomic data which they had collected in the drug development process.

To be honest, it was a very slow start. Companies had many understandable concerns about submitting additional data to the FDA, outside of an official drug review. They were afraid that the agency would act prematurely on the data, create more work for the companies, or create obstacles to drug development. It took a few years for the agency to allay those fears.

Today, FDA’s Voluntary Data Exchange program has dozens of submissions from developer companies and there have been several meetings that enable FDA reviewers to learn about the technology in order to understand how to apply it in the review process while enabling developer companies to gain critical feedback from reviewers about how to structure the data in a new drug application.

And perhaps most encouraging for patients, these voluntary submissions are now moving into actual new drug applications so that advances in genomics can be utilized in new therapies.

For the agency, genomics represents a challenge, as well as a unique opportunity to integrate some key review functions. As most of you probably know, within the FDA there is one center that evaluates drugs and another one that evaluates medical devices.

As determined by statute, the regulatory approach to granting pre-market approval for drugs and biologics is different from the one which applies to medical devices. But personalized medicine in the treatment of disease requires the integration of drugs and diagnostics. And in terms of the progress that is possible, the closer the integration of a drug and diagnostic, the greater the chance that we will see early identification of the populations who can be identified or eliminated as candidates for a particular FDA- approved treatment.

As commissioner, it is clear to me that we need to develop a consistent, comprehensive and integrated approach to the evaluation and regulation of medical products which separately, and in combination, comprise the practice of personalized medicine.

We know for developers to make a substantial investment in this still-evolving arena, they need clear guidelines setting out our expectations and approval standards. One important step in that direction is likely to come before the end of this year when we issue a draft guidance on biomarker qualification. This will enable developers to gain a clear picture of the criteria the FDA will use to vet the usefulness of biomarkers in the evaluation of clinical trial data.

We are also developing a draft guidance that will establish a regulatory pathway for co-development of new drugs and diagnostics, so that new diagnostics can be used to shape clinical trials of new drug therapies.

We look forward to working in close collaboration with Dr. Collins and his team at NIH to identify the knowledge gaps which may prevent us making critical connections between a particular characteristic, a therapeutic intervention and an outcome. When we are able to connect these dots, we can develop a strategy for funding the needed research to fill the gap.

We also need to focus on the important discoveries that we might make by mining the information we already have. New biomarkers which can identify the patient sub-populations most likely to have a positive response or an adverse reaction to a drug can be applied to applications that never made it through the FDA review process. By viewing the data from unsuccessful past trials through the lens of new biomarkers, it may be possible to turn past failures into future successes.

And, as I’ve touched on today, there are already many compelling examples of how new diagnostics are being applied to drugs and biologics that are already on the market, resulting in enhanced safety and effectiveness for patients. Those are success we will build on.

In a similar sense, we know government agencies, insurance companies and major health care providers already process a vast storehouse of valuable patient data. If we can learn to mine that data in a way that is effective and carries the necessary protections of patient privacy we may begin to recognize the critical patterns of patient response that will lead to safer and more effective therapies.

The term “personalized medicine” can mean many different things, from the development of foods that are customized to work with your own metabolism, to the creation of a personal map that can chart a course to avoid inherited disease, to the prospect of health care savings driven by a knowledge of which interventions are most effective for the greatest number of people.

For the FDA, however, the term has a very distinct meaning: it is the application of genomics in the development of medical products that are safer and more effective for the public.

As FDA Commissioner, one of my priorities is building on the strong foundation already established by the professional staff in our Offices of Drug Evaluation, Devices and Biologics. And while I don’t yet have a specific answer to the question “how do we accelerate our path to the future and its potential”, I do know that the approach we take now will determine our way forward.

Regulatory agencies are not known for being flexible, but that is exactly what we need to be. At FDA, this starts with the recognition that incorporating genomics into medical product review requires an interagency, multi-disciplinary effort that transcends the boundaries of any existing center. In order to be truly effective, we need to develop a regulatory framework that reflects the task ahead.

Regulatory agencies are not known for being collaborative, but that is exactly what we need to be. At FDA, this means increasing efforts to reach out to industry in order to identify existing obstacles to innovation and, together, finding ways to maneuver around them.

It means working in partnership with our government colleagues in research, oversight, enforcement and other key areas to identify knowledge gaps and fill them; identify confidence deficits and address them.

Regulatory agencies are not known for their openness and FDA, in particular, has gained a reputation for being a bureaucracy-bound “black box.” But we must be more transparent and endeavor to help the public understand the rationale and reasoning behind the decisions we make which have such far-reaching impacts on public health.

Regulatory agencies are not known for being clear, but that is exactly what we need to be. Just as few runners would show up for a race without knowing the distance to the finish line, medical product companies will not make large scale investments in the science and technology that can lead to safer and more effective therapies, until they know what we require of them in the review process.

Through voluntary data exchange, published guidance, regulation, and every other method of communication available to us, we will establish a clear and illuminated regulatory pathway to product approval.

This all sounds very ambitious, I know. But fundamental biology- the very foundation of genomics—teaches us that successful organisms are successful because they do one thing very well: they adapt.

Building on the wise words of Albert Einstein, when everything has changed, our thinking must change as well. Shifting paradigms and creating new models is not easy.

But I believe that a future that provides safer and more effective therapies for all of us is well worth the effort.